The invention relates to novel sulfonylaminophosphinic and sulphonylaminophosphonic acid derivatives, processes for their preparation and use thereof as pharmaceuticals.
The present application claims priority under 35 U.S.C. xc2xa7 119 to German applications No. 19831980.0 filed Jul. 16, 1998, and No. 19921680.0 filed May 12, 1999. Both priority applications are entirely incorporated herein by reference.
The applications EP 0 606 046, WO 95/35276 and WO 96/27583 describe arylsulfonamidohydroxamic acids and their action as matrix metalloproteinase inhibitors. Specific arylsulfonamidocarboxylic acids are used as intermediates for the preparation of thrombin inhibitors (EP 0 468 231) and aldose reductase inhibitors (EP 0 305 947). The application EP 0 757 037 also describes the action of sulfonylaminocarboxylic acid derivatives as metalloproteinase inhibitors. The arylsulfonyl group has furthermore proved to be an effective protective group of the amino function of xcex1-aminocarboxylic acids. R. Roemmele, H. Rapoport, 53 J. ORG. CHEM. 2367 (1988).
In the attempt to find efficacious compounds for the treatment of connective tissue disorders, it has now been found that the sulfonylaminophosphinic and -phosphonic acid derivatives according to the invention are strong inhibitors of metalloproteinases. Particular value is placed here on the inhibition of stromelysin (matrix metalloproteinase 3, xe2x80x9cMMP-3xe2x80x9d), of neutrophil collagenase (xe2x80x9cMMP-8xe2x80x9d) and of aggrecanase, since these enzymes are involved to a considerable extent in the degradation of proteoglycans, as important constituents of the cartilaginous tissue. A. J. Fosang et al., 98 J. CLIN. INVEST. 2292 (1996).
The pathological loss of aggrecan, the main proteoglycan of the cartilage, includes proteolytic cleavages in its interglobular domain. Amino acid sequence analyses of proteoglycan metabolites, isolated from the synovial fluid of patients who are suffering from injury to a joint, from osteoarthrosis or from an inflammatory joint condition, showed that a proteolytic cleavage preferably takes place between the amino acids Glu373 and Ala374 in the interglobular domain of human aggrecan. Lohmander et al., 36 ARTHRITIS RHEUM. 1214 (1993). Until now, it was not yet possible to identify the proteolytic activity which is responsible for this cleavage. It is designated as xe2x80x9caggrecanasexe2x80x9d and can be included in the metalloproteinases family.
The detection of the expression of MT1-MMP in human cartilaginous tissue for the first time (Bxc3xcttner et al., 40 ARTHRITIS RHEUM. 704 (1997)), combined with the proof that the catalytic domain of this enzyme cleaves at the xe2x80x9caggrecanasexe2x80x9d cleavage site in the recombinant aggrecan fusion protein rAgg1mut (Bxc3xcttner et al., 333 BIOCHEM. J. 159 (1998)), led to the testing of the strong matrix metalloproteinase inhibitors described here with respect to their action against an xe2x80x9caggrecanasexe2x80x9d activity. It was possible here to show using various assay systems that the sulfonylaminophosphinic and -phosphonic acid derivatives are also strong inhibitors for the xe2x80x9caggrecanasexe2x80x9d activity.
The invention therefore relates to the compounds of the formula I 
stereoisomeric forms thereof, and physiologically tolerable salts thereof, where
(A.) R1 is
1. phenyl;
2. phenyl, which is mono- or disubstituted by
2.1. (C1-C6)-alkyl,
2.2. hydroxyl,
2.3. (C1-C6)-alkyl-C(O)xe2x80x94Oxe2x80x94,
2.4. (C1-C6)-alkyl-Oxe2x80x94,
2.5. (C1-C6)-alkyl-Oxe2x80x94(C1-C4)-alkyl-Oxe2x80x94,
2.6. halogen,
2.7. xe2x80x94CF3,
2.8. xe2x80x94CN,
2.9. xe2x80x94NO2,
2.10. HOxe2x80x94C(O)xe2x80x94,
2.11. (C1-C6)-alkyl-Oxe2x80x94C(O)xe2x80x94,
2.12. methylenedioxo,
2.13. R4xe2x80x94(R5)Nxe2x80x94C(O)xe2x80x94,
2.14. R4xe2x80x94(R5)Nxe2x80x94, or
2.15 a heteroaromatic described under A.3.1 to A.3.16;
3. a heteroaromatic described under A.3.1 to A.3.16, which is unsubstituted or substituted by one or more radicals described under A.2.1 to A.2.15,
3.1. pyrrole,
3.2. pyrazole,
3.3. imidazole,
3.4. triazole,
3.5. thiophene,
3.6. thiazole,
3.7. oxazole,
3.8. isoxazole,
3.9. pyridine,
3.10. pyrimidine,
3.11. pyrrolidine,
3.12. indole,
3.13. benzothiophene,
3.14. benzimidazole,
3.15. benzoxazole, or
3.16. benzothiazole; or
4. xe2x80x94Oxe2x80x94(C1-C6)-alkyl;
(B.) R2, R4 and R5 independently of one another are identical or different and are
1. a hydrogen atom;
2. (C1-C6)-alkyl-;
3. HOxe2x80x94C(O)xe2x80x94(C1-C6)-alkyl-;
4. phenyl- (CH2)nxe2x80x94, in which phenyl is unsubstituted or mono- or disubstituted with radicals described under A.2.1 to A.2.15, or is substituted by xe2x80x94NHxe2x80x94C(O)xe2x80x94(C1-C3)-alkyl, and n is the integer zero, 1, or 2;
5. picolyl; or
6. R4 and R5, together with the nitrogen to which they are bonded, form a 4- to 7-membered ring, and the ring is unsubstituted, or a carbon atom in the ring is replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NHxe2x80x94, or two adjacent carbon atoms of the 4- to 7-membered ring are part of a benzyl radical;
(C.) R and R3 are identical or different and are
1. a hydrogen atom;
2. (C1-C10)-alkyl-, in which alkyl is unsubstituted or monosubstituted by xe2x80x94OH;
3. (C2-C10)-alkenyl-, in which alkenyl is linear or branched;
4. R2xe2x80x94Oxe2x80x94(C1-C6)-alkyl-;
5. R2xe2x80x94S(O)nxe2x80x94(C1-C6)-alkyl-, where n is the integer zero, 1, or 2;
6. R2xe2x80x94S(O)(xe2x95x90NH)xe2x80x94(C1-C6)-alkyl-;
7. a radical of formula IIo 
in which n is the integer zero, 1, or 2, and W is a nitrogen, oxygen, or sulfur atom;
8. phenyl-(CH2)mxe2x80x94, in which m is the integer zero, 1, 2, 3, 4, 5, or 6, wherein the xe2x80x94(CH2)mxe2x80x94 chain is unsubstituted or monosubstituted by xe2x80x94OH, and wherein phenyl is unsubstituted or mono- or disubstituted by
8.1 radicals described under A.2.1 to A.2.15,
8.2 xe2x80x94Oxe2x80x94(CH2)m-phenyl, in which phenyl is unsubstituted or mono- or disubstituted with radicals described under A.2.1 to A.2.15, and m is the integer zero, 1, 2, 3, 4, 5, or 6,
8.3 xe2x80x94C(O)xe2x80x94(CH2)m-phenyl, in which phenyl is defined under C.8.2;
9. heteroaryl-(CH2)mxe2x80x94, in which heteroaryl is defined under A.3.1 to A.3.16, m is defined under C.8, the xe2x80x94(CH2)mxe2x80x94 chain is unsubstituted or monosubstituted by xe2x80x94OH, and heteroaryl is unsubstituted or mono- or disubstituted by
9.1 radicals described under A.2.1 to A.2.15,
9.2 xe2x80x94CH(O),
9.3 xe2x80x94SO2-phenyl, in which phenyl is unsubstituted or substituted as defined under C.8.2 or C.8.3,
9.4 xe2x80x94Oxe2x80x94(CH2)m-phenyl;
10. xe2x80x94(CH2)mxe2x80x94P(O)(OH)xe2x80x94(C1-C3)-alkyl, in which m is defined under C.8;
11. a characteristic radical of an amino acid;
12. R6xe2x80x94C(O)xe2x80x94(C0C6)-alkyl- in which R6 is
12.1. a hydrogen atom,
12.2. (C1-C6)-alkyl-,
12.3. phenyl, which is unsubstituted or substituted with one or more radicals described under A.2.1 to A.2.15,
12.4. heteroaryl, which is defined under A.3.1 to A.3.16, and is unsubstituted or substituted with one or more radicals described under A.2.1 to A.2.15, or is substituted by xe2x80x94(C1-C4)-alkyl-COOH,
12.5. xe2x80x94OH,
12.6. xe2x80x94OR2, in which R2 has the meaning described under B.1 to B.6,
12.7. xe2x80x94NR4xe2x80x94(R5), in which R4 and R5 are defined under B.1 to B.6,
12.8. heteroaryl-(CH2)mxe2x80x94NHxe2x80x94, in which heteroaryl is defined under A.3.1 to A.3.16, and is unsubstituted or substituted with one or more radicals described under A.2.1 to A.2.15, and m is defined under C.8,
12.9. R4xe2x80x94(R5)Nxe2x80x94NHxe2x80x94, in which R4 and R5 are defined under B.1 to B.6,
12.10. HOxe2x80x94C(O)xe2x80x94CH(R3)xe2x80x94NHxe2x80x94, in which R3 is defined under C.1 to C.11;
13. xe2x80x94(CH2)pxe2x80x94N(R9)(R10), in which p is an integer zero, 1, 2, 3, or 4, in which R9 and R10 are identical or different and are
13.1. a hydrogen atom,
13.2. phenyl-(CH2)mxe2x80x94, in which phenyl is unsubstituted or mono- or disubstituted with radicals described under A.2.1 to A.2.15, and m is the integer zero, 1, 2, or 3,
13.3. Rxxe2x80x94C(O)xe2x80x94, in which Rx is
3.1 (C1-C6)-alkyl-,
3.2 (C2-C6)-alkenyl-,
3.3 phenyl-(CH2)mxe2x80x94, in which phenyl is unsubstituted or mono- or disubstituted with radicals described under A.2.1 to A.2.15, and m is the integer zero, 1, 2, or 3, or
3.4 heteroaryl-(CH2)mxe2x80x94, in which heteroaryl is defined under A.3.1 to A.3.16,
13.4. Rxxe2x80x94Oxe2x80x94C(O)xe2x80x94, in which Rx is defined under C.13.3,
13.5. Rxxe2x80x94CH(NH2)xe2x80x94C(O)xe2x80x94, in which Rx is defined under C.13.3,
13.6. R8xe2x80x94N(R7)xe2x80x94C(O)xe2x80x94, in which R8 is
6.1 a hydrogen atom
6.2 (C1-C6)-alkyl-,
6.3 phenyl-(CH2)m, in which phenyl is unsubstituted or mono- or disubstituted with radicals described under A.2.1 to A.2.15, and m is the integer zero, 1, 2, or 3, or
6.4 heteroaryl-(CH2)m, in which heteroaryl is defined under A.3.1 to A.3.16, and is unsubstituted or substituted with one or more radicals described under A.2.1 to A.2.15, m is the integer zero, 1, 2, or 3, and in which R7 is a hydrogen atom or (C1-C6)-alkyl-, or in which R7 and R8, together with the nitrogen atom to which they are bonded, form a 4- to 7-membered ring, and the ring is unsubstituted or a carbon atom in the ring is replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NHxe2x80x94,
13.7. Rxxe2x80x94SO2xe2x80x94, in which Rx is defined under C.13.3,
13.8. Rxxe2x80x94NHxe2x80x94C(xe2x95x90NR7)xe2x80x94, in which Rx is defined under C.13.3 and R7 is defined under C.13.6.4, or Rx and R7 are
8.1 (C1-C6)-alkyl-C(O)xe2x80x94,
8.2 xe2x80x94NO2 or
8.3 xe2x80x94SO2xe2x80x94(CH2)q-phenyl, in which phenyl is unsubstituted or mono- or disubstituted with radicals described under A.2.1 to A.2.15, and q is the integer zero, 1, 2, or 3,
13.9. xe2x80x94SO2xe2x80x94(CH2)q-phenylxe2x80x94phenyl, in which each phenyl independently is unsubstituted or mono- or disubstituted with radicals described under A.2.1 to A.2.15, and q is the integer zero, 1, 2, or 3, or
13.10. a radical of formula IIp 
in which m is the integer zero, 1, 2, or 3, and W is a nitrogen atom or sulfur atom, or
R9 and R10, together with the nitrogen atom to which they are bonded, form a ring chosen from radicals of the subformulae IIa to IIn, 
where r is the integer 1 or 2, R11 is a radical described under A.2.1 to A.2.15, R7 is defined under C.13.6.4, and m is defined under C.13.2, and a carbon atom in the ring is replaced by zero or one heterospecies chosen from oxygen, sulfur, or nitrogen atom which is unsubstituted or monosubstituted with R2;
14. xe2x80x94OH;
15. xe2x95x90O;
16. (C1-C6)-alkyl-; or
in the compound of formula I, a xe2x80x94C(R)(R3)xe2x80x94 radical is optionally replaced by xe2x80x94NHxe2x80x94 or xe2x80x94NR2xe2x80x94 in which R2 is defined under B.1 to B.6;
(D.) t is an integer 1, 2, 3, or 4;
(E.) R2 and R3 together form a ring with an exocyclic phosphinic or phosphonic acid radical of the subformula II 
in which r is the integer zero, 1, 2, or 3, and one carbon atom in the ring of the radical of subformula II is replaced by zero or one heterospecies chosen from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94(R7)Nxe2x80x94, in which R7 is
1. a hydrogen atom;
2. (C1-C6)-alkyl;
3. phenyl, in which phenyl is unsubstituted or substituted with one or more radicals described under A.2.1 to A.2.15;
4. benzyl, in which benzyl is unsubstituted or substituted with one or more radicals described under A.2.1 to A.2.15; or
5. R2Nxe2x80x94C(xe2x95x90NH)xe2x80x94 where R2 has the meaning described under B.1 to B.6, and the carbon atoms in the ring of the subformula II are unsubstituted or mono- or polysubstituted by (C1-C6)-alkyl-, phenyl-, phenyl-(CH2)mxe2x80x94 or HOxe2x80x94, or combinations thereof;
(F.) U is xe2x80x94SO2xe2x80x94 or xe2x80x94COxe2x80x94;
(G.) Y1 and Y2 are identical or different and independently of one another are
a) a hydrogen atom;
b) xe2x80x94OH;
c) xe2x80x94(C1-C4)-alkyl, in which alkyl is linear or branched;
d) xe2x80x94(CH2)u-phenyl, in which u is zero or 1;
e) xe2x80x94Oxe2x80x94(C1-C4)-alkyl, in which alkyl is linear or branched; or
f) xe2x80x94Oxe2x80x94(CH2)s-phenyl, in which s is zero or 1;
(H.) A is
a) a covalent bond;
b) xe2x80x94Oxe2x80x94;
c) xe2x80x94CHxe2x95x90CHxe2x80x94; or
d) xe2x80x94Cxe2x89xa1Cxe2x80x94;
(I.) B is
a) xe2x80x94(CH2)mxe2x80x94, in which m is defined under C.13.2;
b) xe2x80x94Oxe2x80x94(CH2)p, in which p is an integer from 1 to 5; or
c) xe2x80x94CHxe2x95x90CHxe2x80x94; and
(J.) X is xe2x80x94CHxe2x95x90CHxe2x80x94, an oxygen atom, or a sulfur atom.
A preferred compound of the formula I is one where
R1 is
1. phenyl;
2. phenyl which is monosubstituted by
2.1. (C1-C5)-alkyl-,
2.2. xe2x80x94OH,
2.3. xe2x80x94C(O)xe2x80x94OH,
2.4. xe2x80x94Oxe2x80x94(C1-C6)-alkyl,
2.5. pyrrolidone,
2.6. halogen, or
2.7. xe2x80x94CF3; or
3. xe2x80x94Oxe2x80x94(C1-C6)-alkyl;
R2, R4 and R5 are identical or different and are a hydrogen atom or (C1-C6)-alkyl-;
R is a hydrogen atom;
R3 is
1. (C1-C6)-alkyl-, in which alkyl is unsubstituted or monosubstituted by xe2x80x94OH,
2. R2xe2x80x94S(O)nxe2x80x94(C1-C6)-alkyl-, in which R2 is (C1-C6)-alkyl- or phenyl-(CH2)nxe2x80x94, and n is the integer zero or 1;
3. xe2x80x94(CH2)m-phenyl, in which phenyl is unsubstituted or mono- or disubstituted with radicals described under A.2.1 to A.2.15 in the original definition of the compound of formula I, the xe2x80x94(CH2)mxe2x80x94 chain is unsubstituted or monosubstituted by xe2x80x94OH, and m is the integer 1, 2, 3, 4, or 5;
4. xe2x80x94(CH2)m-heteroaryl, in which heteroaryl has the meaning mentioned under A.3.3, A.3.5, A.3.6, A.3.9, or A.3.11 in the original definition of the compound of formula I, and is unsubstituted or substituted with one or more radicals described under A.2.1 to A.2.15 in the original definition of the compound of formula I, the xe2x80x94(CH2)mxe2x80x94 chain is unsubstituted or monosubstituted by xe2x80x94OH, and m is the integer 1, 2, 3, or 4;
5. a characteristic radical of an amino acid;
6. xe2x80x94(CH2)pxe2x80x94N(R9)(R10), in which p is the integer zero, 1, or 2 in which R9 and R10 are identical or different and are a hydrogen atom or xe2x80x94SO2xe2x80x94(CH2)q-phenylxe2x80x94phenyl, in which each phenyl independently is unsubstituted or mono- or disubstituted with radicals described under A.2.1 to A.2.15 in the original definition of the compound of formula I, and q is the integer zero, 1, 2, or 3; or
7. R6xe2x80x94C(O)xe2x80x94, in which R6 is
7.1. xe2x80x94OH,
7.2. R2Oxe2x80x94, in which R2 is defined under B.1 to B.6 in the original definition of the compound of formula I, or
7.3. R4xe2x80x94(R5)Nxe2x80x94, in which R4 and R5 are defined under B.1 to B.6 in the original definition of the compound of formula I;
8. a hydrogen atom;
9. xe2x80x94OH;
10. xe2x95x90O; or
11. (C1-C6)-alkyl-; or
in the compound of formula I, a xe2x80x94C(R)(R3)xe2x80x94 radical is optionally replaced by xe2x80x94NHxe2x80x94 or xe2x80x94NR2xe2x80x94, in which R2 is defined under B.1 to B.6 in the original definition of the compound of formula I; and
t is an integer 1, 2, 3, or 4;
U is xe2x80x94SO2xe2x80x94;
Y1 is xe2x80x94OH;
Y2 is
a) xe2x80x94Oxe2x80x94(C1-C4)-alkyl, in which alkyl is linear or branched,
b) xe2x80x94OH, or
c) xe2x80x94(C1-C4)-alkyl, in which alkyl is linear or branched;
A is a covalent bond or xe2x80x94Oxe2x80x94;
B is a covalent bond or xe2x80x94(C1-C4)-alkyl; and
X is xe2x80x94CHxe2x95x90CHxe2x80x94.
A particularly preferred compound of the formula I is one where
R1 is phenyl which is monosubstituted by halogen;
R2 is a hydrogen atom;
R is a hydrogen atom;
R3 is
1. (C1-C4)-alkyl-;
2. -phenyl, in which phenyl is unsubstituted or mono- or disubstituted by xe2x80x94CF3 or xe2x80x94COOH;
3. a hydrogen atom;
4. xe2x80x94OH; or
5. xe2x80x94NHxe2x80x94SO2-phenylxe2x80x94phenyl, in which each phenyl independently is unsubstituted or substituted by one ore more identical or different halogen atoms;
t is an integer 1, 2, 3, or 4;
U is xe2x80x94SO2xe2x80x94;
Y1 and Y2 are identical or different and are xe2x80x94OH or xe2x80x94Oxe2x80x94CH3;
A is a covalent bond;
B is a covalent bond or xe2x80x94(CH2)oxe2x80x94, in which o is 1, 2, or 3; and
X is CHxe2x95x90CHxe2x80x94.
Particularly preferred compounds are (R)- [1-(4xe2x80x2-chlorobiphenyl-4-sulfonyl-amino)-2-methylpropyl]phosphonic acid, dimethyl [3-(4xe2x80x2-chlorobiphenyl-4-sulfonylamino)-1-hydroxy-3-(4-trifluoromethylphenyl)propyl]phosphonate, [1-(4xe2x80x2-chlorobiphenyl4-sulfonylamino)-3-methylbutyl]phosphonic acid, stereoisomeric forms thereof, and physiologically tolerable salts of any of the foregoing.
The expression xe2x80x9cR4 and R5 together with the ring amino group form a 4- to 7-membered ring and/or one of the carbon atoms is replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NHxe2x80x94xe2x80x9d is understood as meaning radicals which are derived, for example, from azetidine, pyrrole, pyrroline, pyridine, azepine, piperidine, oxazole, isoxazole, imidazole, indoline, pyrazole, thiazole, isothiazole, diazepine, thiomorpholine, pyrimidine or pyrazine. The term xe2x80x9chalogenxe2x80x9d is understood as meaning fluorine, chlorine, bromine or iodine. The term xe2x80x9calkylxe2x80x9d or xe2x80x9calkenylxe2x80x9d is understood as meaning hydrocarbon radicals whose hydrocarbon chains are linear, branched, or cyclic, unless otherwise indicated. Cyclic alkyl radicals are, for example, 3- to 6-membered monocyclic systems such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The alkenyl radicals can furthermore also contain a number of double bonds.
When a radical is multisubstituted with other radicals, said other radicals are understood to be independently chosen, being identical or different from each other. For example, in the phrase xe2x80x9ca heteroaromatic . . . which is unsubstituted or substituted by one or more radicals described under A.2.1 to A. 2.15,xe2x80x9d it is intended that said radicals may be mixed and matched, with the identity of one radical having no bearing on the identity of another. Similarly, when a radical is disubstituted with other radicals, said other radicals are identical or different.
The general structural formula of xcex1-amino acids is as follows: 
The xcex1-amino acids differ from one another by the radical R, which in the context of the present application is designated as a xe2x80x9ccharacteristic radicalxe2x80x9d of an amino acid.
The starting substances for the chemical reactions are known or can be easily prepared by methods known from the literature. The aminophosphinic and -phosphonic acids used as starting substances for the synthesis of the compounds according to the invention are, if not commerically obtainable in the individual case, synthesizable according to known methods (R. S. Rogers, M. K. Stern, SYNLETT, 708 (1992); P. P. Giannousis, P. A. Bartlett, 30 J. MED. CHEM. 1603 (1987); J. P. Genet, M. Uziel, A. M. Touzin, S. Roland, S. Thorimbert, S. Tanier, 33 TETRAHEDRON LETT. 77 (1992); E. K. Baylis, C. D. Campbell, J. G. Dingwall, 1 J. CHEM. SOC. PERKIN TRANS. 2845 (1984)).
The invention furthermore relates to a process for the preparation of the compounds of the formula I and/or a stereoisomeric form of the compounds of the formula I and/or of a physiologically tolerable salt of the compounds of the formula I, which comprises
a) reacting an aminophosphinic or -phosphonic acid of the formula III 
in which R2, Y1, Y2, R, and R3 are as defined in formula I, with a sulfonic acid or carbonyl derivative of the formula IV 
in which R1, A, X, U, and B are as defined in formula I and Z is a halogen atom, imidazolyl or xe2x80x94OR8, in which R8 is a hydrogen atom, (C1-C6)-alkyl, phenyl or benzyl, wherein said alkyl, phenyl, or benzyl is independently unsubstituted or substituted, in the presence of a base or optionally of a dehydrating agent to give a compound of the formula I, or
b) reacting an aminophosphinic or -phosphonic acid ester of the formula (V) 
in which R2, R3, t, Y2 and R8 have the abovementioned meaning, with a sulfonic acid or carbonyl derivative of the formula IV to give a compound of the formula VI 
and converting the compound of the formula VI with removal of the radical R8, preferably in the presence of a base or acid, into a compound of the formula I, or
c) reacting the compound of the formula VII 
where n is the integer zero, 1 or 2, with the aid of a protective group E to give a compound of the formula VIII 
and converting the compound of the formula VIII, using a compound of the formula IV into a compound of the formula IX 
and then converting the compound of the formula IX, with removal of the protective group E and of the radical R8 with the aid of suitable cleavage reagents, into the compound of the formula I, or
d) separating a compound of the formula I prepared by one of the processes a), b) or c), which on account of its chemical structure occurs in enantiomeric forms, into the pure enantiomers by salt formation with enantiomerically pure acids or bases, chromatography on chiral stationary phases or derivatization by means of chiral enantiomerically pure compounds such as amino acids, separation of the diastereomers thus obtained, and removal of the chiral auxiliary groups, or
e) isolating the compound of the formula I prepared by one of the processes a), b), c) or d) either in free form or, in the case of the presence of acidic or basic groups, converting it into physiologically tolerable salts.
Suitable protective groups E used for this are preferably the N-protective groups customary in peptide chemistry, for example protective groups of the urethane type, benzyloxycarbonyl (Z), t-butoxycarbonyl (xe2x80x9cBocxe2x80x9d), 9-fluorenylmethoxycarbonyl (xe2x80x9cFmocxe2x80x9d), allyloxycarbonyl (xe2x80x9cAlocxe2x80x9d) or of the acid amide type, in particular formyl, acetyl or trifluoroacetyl, and of the alkyl type, for example benzyl.
Compounds of the formula III employed, in which R2 is a hydrogen atom and R3 is the characteristic radical of an amino acid, are preferably the characteristic radicals of the following naturally occurring xcex1-amino acids: glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid and aspartic acid. Compounds of the formula III employed, in which R2 is a hydrogen atom and R3 is the characteristic radical of an amino acid, are preferably the characteristic radicals, for example, of the following non-naturally occurring amino acids: 2-aminoadipic acid, 2-aminobutyric acid, 2,4-diaminobutyric acid, 2-aminoisobutyric acid, 2,3-diaminopropionic acid, 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2-amino-pimelic acid, phenylglycine, 3-(2-thienyl)alanine, 3-(3-thienyl)alanine, 2-(2-thienyl)glycine, 2-aminoheptanoic acid, pipecolic acid, hydroxylysine, sarcosine, N-methylisoleucine, 6-N-methyllysine, N-methylvaline, norvaline, norleucine, omithine, alloisoleucine, allothreonine, 4-hydroxyproline, 3-hydroxyproline, allohydroxylysine, 3-(2-naphthyl)alanine, 3-(1-naphthylalanine), homophenylalanine, homocysteine, homocysteic acid, homotryptophan, cysteic acid, 3-(2-pyridyl)alanine, 3-(3-pyridyl)alanine, 3-(4-pyridyl)alanine, citrulline, phosphinothricin, 4-fluorophenylalanine, 3-fluorophenylalanine, 2-fluorophenylalanine, 4-chlorophenylalanine, 4-nitrophenylalanine, 4-aminophenylalanine, cyclohexylalanine, 5-fluorotryptophan, 5-methoxytryptophan, methionine sulfone, methionine sulfoxide or NH2xe2x80x94NHxe2x80x94CONH2, if appropriate substituted. In the case of naturally but also of non-naturally occurring amino acids which have a functional group such as amino, hydroxyl, carboxyl, mercapto, guanidyl, imidazolyl or indolyl in the side chain R3, this group can also be protected.
If there is an imidazole radical in R3, the sulfonic acid derivative of the formula IV employed for the sulfonamide formation, for example, serves as a protective group for the imidazole nitrogen, which can be removed again, in particular in the presence of bases such as sodium hydroxide solution.
To prepare compounds of the formula I in which R2 and R3 together form a ring of the substructure II, the starting substances of the formula III utilized are, for example, 2-methylpropylphosphonic acid, piperidine-2-phosphonic acid, piperazine-2-phosphonic acid or hexahydropyridazine-3-phosphonic acid, it being possible, in particular, for the nitrogen in the 4-position of the piperazine-2-phosphonic acid to be substituted by a protective group Z, for example benzyloxycarbonyl or tert-butoxycarbonyl as described in process variant c) or by a radical R7.
Starting materials used for the preparation of the sulfonic acid derivatives of the formula IV are preferably sulfonic acids or their salts of the formula X, for example 
where R9 is a radical described under 2.1. to 2.15.
For the preparation of the arylsulfonic acids of the formulae Xa and b, the sulfonation process using concentrated sulfuric acid described in Houben-Weyl, METHODEN DER ORGANISCHEN CHEMIE [METHODS OF ORGANIC CHEMISTRY] Volume 9, pp. 450-546 is preferably used, if appropriate in the presence of a catalyst, sulfur trioxide and its addition compounds or halosulfonic acids, such as chlorosulfonic acid. Particularly in the case of the diphenyl ethers of the formula Xb, the use of concentrated sulfuric acid and acetic anhydride as a solvent (cf. C. M. Suter, 53 J. AM. CHEM. SOC. 1114 (1931)), or the reaction with excess chlorosulfonic acid (J. P. Bassin, R. Cremlyn and F. Swinbourne, 72 PHOSPHORUS, SULFUR AND SILICON 157 (1992)) has proven suitable. Sulfonic acids according to the formula Xc, Xd or Xe can be prepared in a manner known per se by reacting the corresponding arylalkyl halide with sulfites such as sodium sulfite or ammonium sulfite in aqueous or aqueous/alcoholic solution, it being possible to accelerate the reaction in the presence of tetraorganoammonium salts such as tetrabutylammonium chloride.
Sulfonic acid derivatives according to formula IV used are, in particular, the sulfonyl chlorides. For their preparation, the corresponding sulfonic acids, also in the form of their salts, such as sodium, ammonium or pyridinium salts, are reacted in a known manner with phosphorus pentachloride or thionyl chloride without or in the presence of a solvent such as phosphorus oxychloride or of an inert solvent such as methylene chloride, cyclohexane or chloroform, in general at reaction temperatures from 20xc2x0 C. up to the boiling point of the reaction medium used.
The reaction of the sulfonic acid derivatives of the formula IV with the aminophosphonic acids of the formulae III, V or VII according to process variants a), b) or c) proceeds advantageously in the manner of the Schotten-Baumann reaction. Suitable bases for this are particularly alkali metal hydroxides such as sodium hydroxide, but also alkali metal acetates, hydrogencarbonates, carbonates and amines. The reaction takes place in water and/or in a water-miscible or immiscible solvent such as tetrahydrofuran (xe2x80x9cTHFxe2x80x9d), acetone, dioxane or acetonitrile, the reaction in general being kept at from xe2x88x9210xc2x0 C. to 50xc2x0 C. If the reaction is carried out in an anhydrous medium, tetrahydrofuran or methylene chloride, acetonitrile or dioxane in the presence of a base, such as triethylamine, N-methylmorpholine, N-ethyl- or diisopropylethylamine, is especially used, possibly in the presence of N,N-dimethylaminopyridine as a catalyst.
In another variant, the aminocarboxylic acids of the formula III, IV or VII can first be converted into their silylated form with the aid of a silylating agent such as bistrimethylsilyltrifluoroacetamide (xe2x80x9cBSTFAxe2x80x9d) and they can then be reacted with sulfonic acid derivatives to give the compounds of the formula I.
The preparation of physiologically tolerated salts from compounds of the formula I capable of salt formation, including their stereoisomeric forms, is carried out in a manner known per se. The phosphonic or phosphinic acids form stable alkali metal, alkaline earth metal or optionally substituted ammonium salts with basic reagents such as hydroxides, carbonates, hydrogencarbonates, alcoholates and also ammonia or organic bases, for example trimethyl- or triethylamine, ethanolamine or triethanolamine or alternatively basic amino acids, for example lysine, ornithine or arginine. If the compounds of the formula I have basic groups, stable acid addition salts can also be prepared using strong acids. Both inorganic and organic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, benzenesulfonic, p-toluenesulfonic, 4-bromo-benzenesulfonic, cyclohexylamidosulfonic, trifluoromethylsulfonic, acetic, oxalic, tartaric, succinic or trifluoroacetic acid are suitable for this.
The invention also relates to pharmaceuticals comprising an efficacious amount of at least one compound of the formula I and/or of a physiologically tolerable salt of the compound of the formula I and/or an optionally stereoisomeric form of the compound of the formula I, together with a pharmaceutically suitable and physiologically tolerable excipient, additive and/or other active compounds and auxiliaries.
On account of the pharmacological properties, the compounds according to the invention are suitable for the prophylaxis and therapy of all those disorders in the course of which an increased activity of matrix-degrading enzymes such as metalloproteinases or aggrecanase is involved. These include degenerative joint disorders such as osteoarthroses, spondyloses, chondrolysis after joint trauma or relatively long joint immobilization after meniscus or patella injuries or torn ligaments. These furthermore also include disorders of the connective tissue such as collagenoses, periodontal disorders, wound healing disorders and chronic disorders of the locomotory apparatus such as inflammatory, immunologically or metabolically related acute and chronic arthritis, arthropathies, myalgias and disorders of the bone metabolism. The compounds of the formula I are furthermore suitable for the treatment of ulceration, atherosclerosis and stenoses. The compounds of the formula I are furthermore suitable for the treatment of inflammations, carcinomatous disorders, tumor metastasis formation, cachexia, anorexia and septic shock. In general, the pharmaceuticals according to the invention are administered orally or parenterally. Rectal or transdermal administration is also possible.
The invention also relates to a process for the production of a pharmaceutical, which comprises bringing at least one compound of the formula I into a suitable administration form using a pharmaceutically suitable and physiologically tolerable excipient and, if appropriate, further suitable active compounds, additives or auxiliaries.
Suitable solid or pharmaceutical preparation forms are, for example, granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions and preparations with protracted release of active compound in the production of which customary auxiliaries such as excipients, disintegrants, binding agents, coating agents, swelling agents, glidants or lubricants, flavorings, sweeteners and solubilizers are used. Frequently used auxiliaries which may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactoprotein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower, groundnut or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol.
The pharmaceutical preparations are preferably prepared and administered in dose units, each unit containing as active constituent a specific dose of the compound of the formula I according to the invention. In the case of solid dose units such as tablets, capsules, coated tablets or suppositories, this dose can be up to approximately 1000 mg, but preferably approximately 50 to 300 mg, and in the case of injection solutions in ampoule form up to approximately 300 mg, but preferably approximately 10 to 100 mg.
For the treatment of an adult patient weighing approximately 70 kg, depending on the efficacy of the compound according to formula I, daily doses of approximately 20 mg to 1000 mg of active compound, preferably, for example, 100 mg to 500 mg, are indicated. Under certain circumstances, however, higher or lower daily doses may also be appropriate. The daily dose can be administered both by single administration in the form of an individual dose unit or else of a number of smaller dose units and by multiple administration of subdivided doses at specific intervals.
1H-NMR spectra have been recorded on a 400 MHz apparatus from Bruker or a 200 MHz apparatus from Varian, as a rule using tetramethylsilane (xe2x80x9cTMSxe2x80x9d) as an internal standard and at room temperature (xe2x80x9cRTxe2x80x9d). The solvents used are indicated in each case. As a rule, final products are determined by mass-spectroscopic methods (FAB-, ESI-MS); the main peak is indicated in each case. Temperatures in degrees Celsius, RT means room temperature (22xc2x0 C. to 26xc2x0 C.). Abbreviations used are either explained or correspond to the customary conventions.